Rapid Relief for Depression, Maybe

Summarized by Robert W. Griffith, MD
November 21, 2006

Summary

The onset of action of antidepressant drugs is disappointingly slow, but an intravenous infusion of ketamine (an anesthetic) produces a good response within two hours that lasts for up to a week.

Introduction

Fifty years ago the treatment of depression was revolutionized by the introduction of two major types of drugs - the monoamine oxidase inhibitors and the tricyclic antidepressants. One of the chief drawbacks of both these types of drugs is their slow onset of action; they require 2 to 3 weeks to exert their beneficial effect. In spite of intense efforts, and the introduction of newer antidepressants (e.g. the serotonin receptor reuptake inhibitors, or SSRIs), this delay in the onset of action has not been overcome.

However, a breakthrough has recently occurred. Intravenous administration of an anesthetic agent - ketamine - has been shown to have an extremely rapid effect on the symptoms of severe depression. A report of the study demonstrating this has been published in the Archives of General Psychiatry, and we summarize the main points here.

What was done

The study was done in 18 hospitalized patients with treatment-resistant major depression at the Nation Institute of Mental Health. They had to have failed at least two adequate antidepressant trials, and be healthy, apart from their depression.

After a 2-week drug-free period they were given an intravenous infusion of saline solution (controls) or 0.5 mg/kg of ketamine hydrochloride, over 40 minutes. One week later they received the alternative treatment, i.e. this was a cross-over study design, each patient receiving saline and ketamine separately, in random order, one week apart.

Assessment of depression was done using the 21-item Hamilton Depression Rating Scale (Ham-D), a widely-recognized and accepted measurement. Ratings were done 60 minutes before the infusion, and at 40, 80, 110, and 230 minutes, as well as 1, 2, 3, and 7 days after the infusion. Additional rating scales were also used - the Beck Depression Inventory and the Brief Psychiatric Rating Scale (BPRS).

A clinical response was defined as a 50% or greater decrease in the Ham-D score from baseline, and remission was defined as a Ham-D score of 7 or lower.

What was found

The 18 patients entering the study had an average age of 47; there were 12 women and 6 men. On average, they had suffered depression off and on for 24 years, with 7 distinct episodes, the present episode having lasted almost 3 years.

Seventeen subjects received ketamine and 14 received saline; 4 weren't given saline after getting a one-week response after ketamine, and one stopped the study for medical reasons after her saline infusion.

Those given ketamine showed significant improvement in depression within 110 minutes of the infusion, which remained significant throughout the following week; 71% had a response, and 29% a remission according to the Ham-D rating on the day after ketamine. Thirty-five percent maintained their response for at least a week.

What these results mean

Ketamine is an anesthetic agent that has a different method of action from the known antidepressants, being an antagonist of N-methyl-D-aspartate receptors. It can be abused as a recreational drug, causing hallucinations and euphoria. Its widespread use as an antidepressant, therefore, is likely to be surrounded by difficulties. However, the value of this study is the demonstration of a remarkable response with a drug having a different mechanism of action from the known effective antidepressants.

The study investigators realize how dramatic their findings are, and emphasize that the drug should only be studied in a research setting and not used clinically, for the present. Other specialists are somewhat wary - they believe that the problems that will certainly arise if ketamine is more widely used will prove insurmountable. Time will tell; further studies will be done with ketamine and its chemical analogs to see if the benefits can be enhanced and the risks reduced. In the meantime, let's enjoy the good news - a significant breakthrough in the battle against severe depression.

Source

• A randomized trial of an N-methyl-D-aspartate antagonist in treatment-resistant depression. CA. Zarate, JB. Singh, PJ. Carlson,  et al. , Arch Gen Psychiatry , 2006, vol. 63, pp. 856--864

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